title: Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.
abstract: Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD.
authors.affiliation: Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. Electronic address: raouf_khalil@hms.harvard.edu.
authors.forename: Raouf A
authors.initials: RA
authors.lastname: Khalil
mesh_terms: D001808:Blood Vessels / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D014652:Vascular Diseases / Q000503:physiopathology*
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen
keywords: 17β-estradiol; 27-hydroxycholesterol; 27HC; Akt; AngII; C-reactive protein; CEE; CRP; CVD; E2; EC; ECM; ELITE; ER; Early versus Late Intervention Trial with Estradiol; Endothelium; Extracellular matrix; FMD; G protein-coupled receptor 30; GPR30; HERS; HSP90; Hypertension; IL-6; KEEPS; Kronos early estrogen prevention study; MAPK; MHT; MI; MMP; MPA; NHS; NO; Nurses’ Health Study; OVX; P4; PCOS; PI(3)K; Post-MW; Pre-MW; Progesterone; RCT; SHR; Sex hormones; T; TMF-α; TXA2; Testosterone; VSM; VSM cell; VSMC; VTE; Vascular smooth muscle; WHI; Women's Health Initiative; angiotensin II; cardiovascular disease; conjugated equine estrogen; eNOS; endothelial cell; endothelial nitric oxide synthase; estrogen receptor; extracellular matrix; flow mediated dilation; heart and estrogen/progestin replacement study; heat shock protein-90; interleukin-6; matrix metalloproteinase; medroxyprogesterone acetate; menopausal hormone therapy; mitogen-activated protein kinase; myocardial infarction; nitric oxide; ovariectomized; phosphatidylinositol 3-kinase; polycystic ovary syndrome; postmenopausal women; premenopausal women; progesterone; protein kinase B; randomized clinical trial; spontaneously hypertensive rat; testosterone; thromboxane A2; tumor necrosis factor-α; vascular smooth muscle; venous thrombo-embolism